Distal margin distance in radical resection of locally advanced rectal cancer after neoadjuvant therapy.

Colorectal cancer has a high incidence and mortality rate in China, with the majority of cases being middle and low rectal cancer. Surgical intervention is currently the main treatment modality for locally advanced rectal cancer, with the common goal of improving oncological outcomes while preserving function. The controversy regarding the circumferential resection margin distance in rectal cancer surgery has been resolved. With the promotion of neoadjuvant therapy concepts and advancements in technology, treatment strategies have become more diverse. Following tumor downstaging, there is an increasing trend towards extending the safe distance of distal rectal margin. This provides more opportunities for patients with low rectal cancer to preserve their anal function. However, there is currently no consensus on the specific distance of distal resection margin.

Replenishment of mitochondrial Na+ and H+ by ionophores potentiates cutaneous wound healing in diabetes.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na+) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na+ transporters have been identified as a functional regulator of regeneration. However, the role of Na+ in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na+ ionophores that were employed to increase intracellular Na+ content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na+ decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na+ ionophores replenish H+ to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na+, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na+ ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.

Adsorption and Degradation of Organics in Wastewater on Municipal Sludge.

Adsorption and degradation of organic compounds on sludge were investigated by comparing activated and inactivated sludge at various dosages, pH values, and temperatures. The organic compounds in wastewater were identified and evaluated through fluorescence spectra. The results show that optimum adsorption occurred as the activated and inactivated sludge concentration was 4000 mg/L at a pH of 7.99 and a temperature of 30 °C. The fluorescence scanning spectrum indicated that activated sludge could remove protein-like organic matter, fulvic acid-like organic matter, and humic acid-like organic matter by 22.1, 9.4, and 41.2%, respectively, via adsorption only or by 25.9, 9.8, and 74.3%, respectively, via adsorption and degradation. Under optimum conditions, by using the good adsorption performance of sludge combined with other sewage treatment technologies, the treatment of high-content organic wastewater can be achieved.

RNA demethylase ALKBH5 promotes colorectal cancer progression by posttranscriptional activation of RAB5A in an m6A-YTHDF2-dependent manner.

BACKGROUND: N6-methyladenosine (m6A) modification is an emerging epigenetic regulatory mechanism in tumourigenesis. Considering that AlkB homolog 5 (ALKBH5) is a well-described m6A demethylase in previous enzyme assays, we aimed to investigate the role of m6A methylation alteration conferred by disturbed ALKBH5 in colorectal cancer (CRC) development. METHODS: Expression of ALKBH5 and its correlation with clinicopathological characteristics of CRC were evaluated using the prospectively maintained institutional database. The molecular role and underlying mechanism of ALKBH5 in CRC were explored using in vitro and in vivo experiments with methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-seq, MeRIP-qPCR, RIP-qPCR and luciferase reporter assays. RESULTS: ALKBH5 expression was significantly upregulated in CRC tissues compared to the paired adjacent normal tissues, and higher expression of ALKBH5 was independently associated with worse overall survival in CRC patients. Functionally, ALKBH5 promoted the proliferative, migrative and invasive abilities of CRC cells in vitro and enhanced subcutaneous tumour growth in vivo. Mechanistically, RAB5A was identified as the downstream target of ALKBH5 in CRC development, and ALKBH5 posttranscriptionally activated RAB5A by m6A demethylation, which impeded the YTHDF2-mediated degradation of RAB5A mRNA. In addition, we demonstrated that dysregulation of the ALKBH5-RAB5A axis could affect the tumourigenicity of CRC. CONCLUSIONS: ALKBH5 facilitates the progression of CRC by augmenting the expression of RAB5A via an m6A-YTHDF2-dependent manner. Our findings suggested that ALKBH5-RAB5A axis might serve as valuable biomarkers and effective therapeutic targets for CRC.

Fasting-mimicking diet synergizes with ferroptosis against quiescent, chemotherapy-resistant cells.

BACKGROUND: More than ten randomized clinical trials are being tested to evaluate the efficacy, effectiveness and safety of a fasting-mimicking diet (FMD) combined with different antitumor agents. METHODS: UMI-mRNA sequencing, Cell-cycle analysis, Label retention, metabolomics, Multilabeling et al. were used to explore mechanisms. A tandem mRFP-GFP-tagged LC3B, Annexin-V-FITC Apoptosis, TUNEL, H&E, Ki-67 and animal model was used to search for synergistic drugs. FINDINGS: Here we showed that fasting or FMD retards tumor growth more effectively but does not increase 5-fluorouracil/oxaliplatin (5-FU/OXA) sensitivity to apoptosis in vitro and in vivo. Mechanistically, we demonstrated that CRC cells would switch from an active proliferative to a slow-cycling state during fasting. Furthermore, metabolomics shows cell proliferation was decreased to survive nutrient stress in vivo, as evidenced by a low level of adenosine and deoxyadenosine monophosphate. CRC cells would decrease proliferation to achieve increased survival and relapse after chemotherapy. In addition, these fasting-induced quiescent cells were more prone to develop drug-tolerant persister (DTP) tumor cells postulated to be responsible for cancer relapse and metastasis. Then, UMI-mRNA sequencing uncovered the ferroptosis pathway as the pathway most influenced by fasting. Combining fasting with ferroptosis inducer treatment leads to tumor inhibition and eradication of quiescent cells by boosting autophagy. INTERPRETATION: Our results suggest that ferroptosis could improve the antitumor activity of FMD + chemotherapy and highlight a potential therapeutic opportunity to avoid DTP cells-driven tumor relapse and therapy failure. FUNDING: A full list of funding bodies can be found in the Acknowledgements section.

Radiological lymph-node size improves the prognostic value of systemic inflammation index in rectal cancer with pathologically negative nodes.

BACKGROUND: The relationship between the radiological lymph node (rLN) size and survival outcome in node-negative rectal cancer is still uncertain. In this study, we aimed to explore the role of enlarged rLN in predicting the survival of node-negative rectal cancers. METHODS: We retrospectively reviewed the records of 722 node-negative rectal cancer who underwent curative resection. Factors associated with DFS (disease-free survival) and CSS (cancer-specific survival) were assessed with univariate and multivariate analysis. Survival analysis was performed according to presence with or without enlarged rLN. Combining rLN with NLR as a new index-inflammation immune score (IIS) for predicting survival. Comparing different models to assess the predictive powers. RESULTS: A total of 119 patients had tumor recurrence and 73 patients died due to cancer. Patients with enlarged rLN (≥5 mm) was significantly associated with better DFS (HR:0.517, 95%CI:0.339-0.787, p = 0.002) and CSS (HR:0.43, 95%CI:0.242-0.763, p = 0.004). The risk factors of recurrence were rLN, neutrophil-lymphocyte ratio (NLR), CEA level, and distance from the anal verge. The risk of recurrence increased by 1.88- and 2.83-fold for the high score in IIS compared with the low and intermediate score group (All p < 0.001). Similarly, the high score in IIS also increased the risk of cancer-specific death. In the model comparison, the AIC and LR were improved by including the rLN into the NLR model for DFS and CSS prediction (All p < 0.05). CONCLUSIONS: Node-negative rectal cancer patients with enlarged rLN had a better survival outcome. IIS might be a more comprehensive and complete inflammation immune index for survival prediction.

Prevalent Pseudoprogression and Pseudoresidue in Patients With Rectal Cancer Treated With Neoadjuvant Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitor (ICI) treatment in patients with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) tumors holds promise in reshaping organ preservation in rectal cancer. However, the benefits are accompanied by distinctive patterns of response, introducing a dilemma in the response evaluation for clinical decision-making. PATIENTS AND METHODS: Patients with locally advanced rectal cancer with MSI-H/dMMR tumors receiving neoadjuvant ICI (nICI) treatment (n=13) and matched patients receiving neoadjuvant chemoradiotherapy (nCRT; n=13) were included to compare clinical response and histopathologic features. RESULTS: Among the 13 patients receiving nICI treatment, in the final radiologic evaluation prior to surgery (at a median of 103 days after initiation of therapy), progressive disease (n=3), stable disease (n=1), partial response (n=7), and complete response (n=2) were observed. However, these patients were later confirmed as having pathologic complete response, resulting in pseudoprogression and pseudoresidue with incidences of 23.1% (n=3) and 76.9% (n=10), respectively, whereas no pseudoprogression was found in the 13 patients receiving nCRT. We further revealed the histopathologic basis underlying the pseudoprogression and pseudoresidue by discovering the distinctive immune-related regression features after nICI treatment, including fibrogenesis, dense lymphocytes, and plasma cell infiltration. CONCLUSIONS: Pseudoprogression and pseudoresidue were unique and prevalent response patterns in MSI-H/dMMR rectal cancer after nICI treatment. Our findings highlight the importance of developing specific strategies for response evaluation in neoadjuvant immunotherapy to identify patients with a good response in whom sphincter/organ-preserving or watch-and-wait strategies may be considered.

Clinical spectrum of rectal cancer identifies hallmarks of early-onset patients and next-generation treatment strategies.

BACKGROUND: The incidence of colorectal cancer is increasing among young adults and more rectal cancers are reported. This study aimed to identify the clinical features specific for early-onset rectal cancer and provide insights on cancer management. METHODS: Early-onset (<50 years) and late-onset (≥50 years) rectal cancer patients from a referral tertiary care center (SYSU cohort) and Surveillance Epidemiology and End Results database (SEER cohort) were included to perform a comprehensive comparison on clinical information. RESULTS: A total of 552 and 80,341 patients with stages I-III rectal cancer were included in the SYSU and SEER cohorts, respectively. In the SYSU cohort, early-onset diseases had significantly higher prevalence of family history of cancer and history of HBV infection and lower incidence of comorbidities (p < 0.05). In addition, early-onset patients presented more frequently with advanced node stage (N2 stage: 16.9 vs. 9.3%, p = 0.017) and high-risk features, including mucinous or signet cell carcinomas (21.8 vs. 12.9%, p = 0.014), poorly differentiated tumors (28.8 vs. 15.4%, p = 0.002), and perineural invasion (14.5 vs. 7.9%, p = 0.027) compared with late-onset patients. However, early-onset patients received more neoadjuvant (18.5 vs. 11.2%, p = 0.032) and adjuvant treatments (71.0 vs. 45.8%, p < 0.001), and they had better overall survival in both SYSU (HR 0.57, 95% CI: 0.34-0.95; p = 0.029) and SEER (HR 0.38, 95% CI: 0.37-0.40; p < 0.001) cohorts. CONCLUSION: Early-onset rectal cancers are distinct from late-onset cases in clinicopathological features, treatment modalities, and outcomes. The clinical trials and studies that are specific for young populations are needed to develop optimal strategies for cancer screening, treatment, and surveillance.

Polymethoxyflavones from citrus peel: advances in extraction methods, biological properties, and potential applications.

Citrus peel, as an effective component of citrus by-products, contains a large number of natural active components, including pectin, vitamins, dietary fiber, essential oil, phenolic compounds, flavonoids, and so on. With the development of the circular economy, citrus peel has attracted extensive concern in the food industry. The exploitation of citrus peel would assist in excavating potential properties and alleviating the environmental burden. Polymethoxyflavones (PMFs) exist almost in citrus peel, which have remarkable biological activities including antioxidant, anti-inflammatory, anti-cancer, and anti-obesity. Therefore, PMFs from citrus peel have the potential to develop as dietary supplements in the near future. Collectively, it is essential to take action to optimize the extraction conditions of PMFs and make the most of the extracts. This review mainly compiles several extraction methods and bioactivities of PMFs from citrus peel and introduces different applications including food processing, pharmaceutical industry, and plant rhizosphere to develop better utilization of citrus PMFs.

Polymethoxyflavones (PMFs) represent sustainable bioactive compounds that profit for circular economy.Valorization of citrus peel PMFs will bring value-added environmental benefits.Novel techniques improve property and extraction efficiency of PMFs.PMFs obtained from citrus peel could be applied to tea or bakery food processing and pharmaceutical industry.

Insight into the dual action mechanism of 3V-PPh3 polymers as carriers and ligands in the Rh/3V-PPh3 heterogeneous catalytic hydroformylation of ethylene to propionaldehyde.

An experimentally confirmed porous vinyl-functionalized PPh3 (3V-PPh3) polymer-supported Rh-based catalyst exhibits the significant advantages of high activity, high stability, and easy separation in the synthesis of propionaldehyde, which fundamentally solves the problem of Rh precious-metal loss. In this paper, the microscopic mechanism and electronic structure characteristics of two kinds of cross-linked 3V-PPh3 polymer-supported Rh-based catalyst were studied by means of quantum chemistry (QC). With 3V-PPh3 as the carrier, stable adsorption configurations of Rh and 3V-PPh3 were investigated, and the results showed that Rh and P had the strongest effects, while the vinyl group enhanced the adsorption strength of Rh. Moreover, it was found that a high concentration of exposed P was beneficial to the dispersion of Rh. With 3V-PPh3 as the ligand, the properties of the HRh(CO)(P-frame)3 complex were investigated, and the results of structure analysis indicated that there were strong interactions between Rh and P, which contributed more to the non-loss of Rh. Among the four different configurations, the Rh-P coplanar configuration of cross-linking mode 2 had the highest Rh-P bond energy. The results of AIM analysis suggested that the Rh-P and Rh-C(CO) bonds involve closed-shell (donor-acceptor) interactions. The Mulliken charge and molecular electrostatic potential results revealed that the Rh activity of the Rh and P non-coplanar configuration was higher in the two cross-linking methods. Hopefully, this work will clarify the structure-activity relationship between 3V-PPh3 polymer and Rh, and provide theoretical guidance for the design and development of high-efficiency heterogeneous catalysts for the hydroformylation of ethylene to propionaldehyde.

Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages.

BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found here that the CSF1R expression was abnormally down-regulated in colorectal cancer (CRC), and its biological functions and underlying mechanisms have become elusive in CRC progression. METHODS: The expression of class III receptor tyrosine kinases in CRC and normal intestinal mucosa was accessed using The Cancer Genome Atlas and Gene Expression Omnibus datasets and was further validated by our tested cohort. CSF1R was reconstructed in CRC cells to identify its biological functions in vitro and in vivo. We compared CSF1R expression and methylation differences between CRC cells and macrophages. Furthermore, a co-culture system was used to mimic a competitive mechanism between CSF1R-overexpressed CRC cells and M2-like macrophages. We utilized a CSF1R inhibitor PLX3397 to ablate M2 TAMs and evaluated its efficacy on CRC treatment in animal models. RESULTS: We found here that the CSF1R is silenced in CRC, and the reintroduced expression of the receptor in CRC cells can be cleaved by caspases and constrain tumor growth in vitro and in vivo, functioning as a tumor suppressor gene. We further identified CSF1R as a novel dependence receptor, which has the potential to act as either a tumor suppressor gene or an oncogene, depending on its activated state. In CRC tumors, CSF1R expression is enriched in TAMs, and its expression is associated with poor prognosis in patients ith CRC. In a co-culture system, CRC cells expressing CSF1R compete with M2-like macrophages for CSF1R ligands, resulting in a decrease in CSF1R activation and cell proliferation in macrophages. Blocking CSF1R by PLX3397 could deplete M2 TAMs and augments CD8+ T cell infiltration, effectively inhibiting tumor growth and metastasis and improving responses to chemotherapy and immunotherapy. CONCLUSION: Our findings revealed that CSF1R is a novel identified dependence receptor silenced in CRC. The silence abalienates its ligands to stimulate CSF1R expressed on M2 TAMs, which is an appealing therapeutic target for M2 TAM depletion and CRC treatment.

Current treatment and surveillance modalities are not sufficient for advanced stage III colon cancer: Result from a multicenter cohort analysis.

OBJECTIVE: We conducted this multicenter cohort study to evaluate the current tumor-node-metastasis staging system and treatment modality by analyzing the survival outcomes of patient groups with stage III and IV colon cancer. PATIENTS AND METHODS: Stage III and IV colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database (SEER cohort) and prospectively maintained Sun Yat-sen University (SYSU) cohort were included in this study. Kaplan-Meier method was used to estimate the cumulative rate of overall survival (OS) between patient groups, and the inverse probability weighting method was used to calculated age and sex-adjusted survival curves. The Cox regression model was used to identify the risk factors for OS. RESULTS: A total of 17,911 and 1135 stage III-IV cases were included in the SEER and SYSU cohorts, respectively. Among them, 1448 and 124 resectable stage IV cases underwent curative-intent treatment in the SEER and SYSU cohorts, respectively. The T4N2b group showed a significantly worse survival outcome compared with the M1a subset receiving curative-intent treatment (HR, 1.46; p < 0.001). This finding was validated in the SYSU cohort, in which the T4N2 group had a worse outcome than that of the M1 group receiving curative-intent treatment (HR, 2.44; p < 0.001). These findings were confirmed in the adjusted survival analysis. In the multivariate analysis, the right-side tumor, poor-undifferentiated tumor, and age over 60 years were identified as independent risk factors for T4N2b patients. Based on this multivariate model, the high-risk T4N2b subgroup had a worse survival outcome compared with resectable M1b patients (HR, 1.24; p = 0.03). CONCLUSION: By comparing stage III with stage IV colon cancer patients, we identified a subgroup of stage III patients at a higher risk of death than more advanced stages, implying that current cancer care modalities are not sufficient for these high-risk substages.

DFT Study on the Chemical Absorption Mechanism of CO2 in Diamino Protic Ionic Liquids.

Diamino protic ionic liquids (DPILs) possess a wide application prospect in the field of acid gas absorption. In this work, two representative DPILs, that is, dimethylethylenediamine 4-fluorophenolate ([DMEDAH][4-F-PhO]) and dimethylethylenediamine acetate ([DMEDAH][OAc]), which had been proved to display favorable CO2 absorption performance in experiments, were selected. Based on the solvation model, the different mechanisms of CO2 absorption by [DMEDAH]+ cations combined with different anions were investigated using the dispersion-corrected density functional theory method. Above all, the possible active sites of the reaction between DPILs and CO2 were analyzed by electrostatic potential (ESP) and electronegativity, and the transition states in each path were searched and verified by frequency calculation and intrinsic reaction coordinate calculation. Furthermore, the Gibbs free energy and reaction heat of each path were calculated, and the free energy barrier and enthalpy barrier diagrams were shown. It was found that the absorption path by the anion of [DMEDAH][4-F-PhO] was favorable in kinetics, while the absorption path by the cation was thermodynamically beneficial. In addition, [DMEDAH][OAc] only showed the possibility of cation absorption, and the mechanism of the transfer of active protons to weak acid anions and the formation of acetic acid molecules was more favorable. Moreover, through the structural analysis, bond order and bond energy calculation, ESP analysis of the ion pair absorption configuration, and comparison with the products of CO2 absorbed by isolated ions, it was found that the interaction between anions/cations and CO2 could weaken or enhance the interaction between anions and cations in different reaction steps. Hopefully, this study is helpful to understand the absorption mechanism of CO2 by DPILs and provides a theoretical basis for the R&D of multi-active site functionalized ILs.

Simple approach for the fabrication of PEDOT-coated Si nanowires.

The synthesis of a conformal poly(3,4-ethylenedioxythiophene) (PEDOT) layer on Si nanowires was demonstrated using a pulsed electrodeposition technique. N-type Si nanowire (SiNWs) arrays were synthesized using an electroless metal-assisted chemical etching technique. The dependence of the SiNW reflection on the concentration of the AgNO3 solution was identified. A reflection of less than 2% over the entire visible spectral range was obtained for these structures, evidencing their excellent antireflective properties. The etched SiNWs nanostructures can be further modified by using a tapering technique, which further preserves the strong light trapping effect. P-type PEDOT was grown on these SiNWs using electrochemical methods. Since the polymerization reaction is a very fast process with regards to monomer diffusion along the SiNW, the conformal deposition by classical, fixed potential deposition was not favored. Instead, the core-shell heterojunction structure was finally achieved by a pulsed deposition method. An extremely large shunt resistance was exhibited and determined to be related to the diffusion conditions occurring during polymerization.

Highly ordered architecture of microRNA cluster.

Although it is known that the placement of genes in a cluster may be critical for proper expression patterns, it remains largely unclear whether the orders of members in an miRNA cluster have biological insights. By investigating the relationship between expression and orders for miRNAs from the oncogenic miR-17-92 cluster, we observed a highly ordered architecture in this cluster. A significant correlation between miRNA expression level and its placement was revealed. More importantly, the placement of these miRNAs is associated with their dysregulation in cancer. Here, we presented the opinion that miRNA clusters are not arranged randomly but show highly ordered architectures, which may have critical roles in physiology and pathology.

Statistical optimization of process variables for antibiotic activity of Xenorhabdus bovienii.

The production of secondary metabolites with antibiotic properties is a common characteristic to entomopathogenic bacteria Xenorhabdus spp. These metabolites not only have diverse chemical structures but also have a wide range of bioactivities of medicinal and agricultural interests. Culture variables are critical to the production of secondary metabolites of microorganisms. Manipulating culture process variables can promote secondary metabolite biosynthesis and thus facilitate the discovery of novel natural products. This work was conducted to evaluate the effects of five process variables (initial pH, medium volume, rotary speed, temperature, and inoculation volume) on the antibiotic production of Xenorhabdus bovienii YL002 using response surface methodology. A 2(5-1) factorial central composite design was chosen to determine the combined effects of the five variables, and to design a minimum number of experiments. The experimental and predicted antibiotic activity of X. bovienii YL002 was in close agreement. Statistical analysis of the results showed that initial pH, medium volume, rotary speed and temperature had a significant effect (P<0.05) on the antibiotic production of X. bovienii YL002 at their individual level; medium volume and rotary speed showed a significant effect at a combined level and was most significant at an individual level. The maximum antibiotic activity (287.5 U/mL) was achieved at the initial pH of 8.24, medium volume of 54 mL in 250 mL flask, rotary speed of 208 rpm, temperature of 32.0°C and inoculation volume of 13.8%. After optimization, the antibiotic activity was improved by 23.02% as compared with that of unoptimized conditions.